We propose to design and synthesize photoaffinity inhibitors of lens aldose reductase and show that these inhibitors will prevent diabetic and other sugar cataract formation more efficiently than the simple, reversible enzyme inhibitors. For example, a known reversible, non-competitive inhibitor such as quercitrin will be modified by addition of a photosensitive, aryl azide-containing moiety to its carbohydrate residue to form an irreversible, light-activated drug. Studies with quercitrin analogues and their syntheitic derivatives indicate that substitution onto the carbohydrate residue does not significantly increase their KI (inhibition constant). Among the potential therapeutic advantages of the photoactivated irreversible inhibitors over the simple, reversible inhibitors are their greater organ specificity, fewer side effects, and lower dosage and frequency of administration requirement to prevent polyol accumulation and consequent cataract formation. The drugs will be tested first by characterizing inhibition of purified lens aldose reductase and crude lens extracts. These initial studies will be followed by measuring the inhibition of aldose reductase and cataract formation in organ culture experiments using both animal and human lenses. The best of these drugs will then be tested as inhibitors of aldose reductase in in vivo experiments using rats. In the final experiments, the slowing or blocking of cataract formation will be studied.